Epithelia serve as the first line of defense of an organism that is constantly exposed to microbes, viruses and toxins. As a first line of defense, any open wound will need to be quickly repaired. Hence it will be advantageous for epithelial cells to be exposed to growth factors so that a quick encounter with these growth factors is possible when the integrity of the epithelial sheet is compromised. This will require such epithelial cells to position their growth factor receptors strategically on their surfaces.
The tight junction (TJ) is the topmost intercellular junction in epithelial cells that is linked to the regulation of paracellular permeability and signal transduction. The TJ is composed of membrane-associated guanylate kinase proteins (MAGUKs) that include Zonula Occluden proteins (ZO-1, ZO-2 and ZO-3). These proteins have been shown to contain nuclear sorting signals and are capable of shuttling between the membrane and nucleus depending on cell density.
In particular, ZO-2 has been shown to be capable of shuttling between the nucleus and cytoplasm. In sparse Madin-Darby Canine Kidney (MDCK) cell cultures, ZO-2 tends to accumulate in the nucleus. In addition, when pig kidney epithelial cells were subjected to environmental stress or growth at 42° C., an increased nuclear staining of ZO-2 was observed. Furthermore, in some tumor cells, TJ proteins were also found inside the nucleus. It has been found that ZO-2 may function as a tumor suppressor by blocking cell cycle progression at the transcription and protein level. Support for the role of ZO-2 as a tumor suppressor also comes from observations that its expression is either lost or decreased in a majority of breast cancer cell lines and adenocarcinomas.
Accordingly, it appears that ZO proteins have been found to translocate to the nucleus when epithelial cells are subjected to external stress such as mechanical injury, heat shock and chemical insults. However, the biological relevance of this accumulation of ZO-2 in the nucleus under such circumstances has however remained somewhat elusive.
Slug is a member of the Snail superfamily of zinc finger transcription factors. Snail and Slug were shown to elicit epithelial-to-mesenchymal transition (EMT) through the direct repression of E-cadherin expression. This process is critical in developmental processes such as gastrulation, neural crest cell migration, organogenesis, as well as in the metastasis of tumors derived from epithelial tissues. EMT is also linked to wound healing, fibroblastic remodeling in mature tissues after injury and tubulogenesis. Hence, studying the mechanisms that regulate the Snail superfamily of transcription factors is important.
There is therefore a need to establish a relationship between ZO-2 and the Snail superfamily of transcription factors and uses for such a relationship.